EP0878713B1 - Méthode et appareil pour corriger l'effet de la température ambiente dans les biodétecteurs - Google Patents

Méthode et appareil pour corriger l'effet de la température ambiente dans les biodétecteurs Download PDF

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EP0878713B1
EP0878713B1 EP98107778A EP98107778A EP0878713B1 EP 0878713 B1 EP0878713 B1 EP 0878713B1 EP 98107778 A EP98107778 A EP 98107778A EP 98107778 A EP98107778 A EP 98107778A EP 0878713 B1 EP0878713 B1 EP 0878713B1
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ambient temperature
biosensors
analyte concentration
measured
recited
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EP0878713A2 (fr
EP0878713A3 (fr
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Dijia Huang
Brenda L. Tudor
Kin-Fai Yip
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Bayer Corp
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Bayer Corp
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/001—Enzyme electrodes
    • C12Q1/005—Enzyme electrodes involving specific analytes or enzymes
    • C12Q1/006—Enzyme electrodes involving specific analytes or enzymes for glucose
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
    • G01N27/26—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating electrochemical variables; by using electrolysis or electrophoresis
    • G01N27/28—Electrolytic cell components
    • G01N27/30—Electrodes, e.g. test electrodes; Half-cells
    • G01N27/327—Biochemical electrodes, e.g. electrical or mechanical details for in vitro measurements
    • G01N27/3271—Amperometric enzyme electrodes for analytes in body fluids, e.g. glucose in blood
    • G01N27/3274—Corrective measures, e.g. error detection, compensation for temperature or hematocrit, calibration
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T436/00—Chemistry: analytical and immunological testing
    • Y10T436/14—Heterocyclic carbon compound [i.e., O, S, N, Se, Te, as only ring hetero atom]
    • Y10T436/142222—Hetero-O [e.g., ascorbic acid, etc.]
    • Y10T436/143333—Saccharide [e.g., DNA, etc.]
    • Y10T436/144444—Glucose

Definitions

  • the present invention relates to a biosensor, and, more particularly, to a new and improved method and apparatus for correcting ambient temperature effect in biosensors.
  • the quantitative determination of analytes in body fluids is of great importance in the diagnoses and maintenance of certain physiological abnormalities. For example lactate, cholesterol and bilirubin should be monitored in certain individuals.
  • the determination of glucose in body fluids is of great importance to diabetic individuals who must frequently check the level of glucose in their body fluids as a means of regulating the glucose intake in their diets. While the remainder of the disclosure herein will be directed towards the determination of glucose, it is to be understood that the procedure and apparatus of this invention can be used for the determination of other analytes upon selection of the appropriate enzyme.
  • the ideal diagnostic device for the detection of glucose in fluids must be simple, so as not to require a high degree of technical skill on the part of the technician administering the test. In many cases, these tests are administered by the patient which lends further emphasis to the need for a test which is easy to carry out. Additionally, such a device should be based upon elements which are sufficiently stable to meet situations of prolonged storage.
  • Methods for determining analyte concentration in fluids can be based on the electrochemical reaction between an enzyme and the analyte specific to the enzyme and a mediator which maintains the enzyme in its initial oxidation state.
  • Suitable redox enzymes include oxidases, dehydrogenases, catalase and peroxidase.
  • glucose is the analyte
  • the reaction with glucose oxidase and oxygen is represented by equation (A).
  • the released hydrogen peroxide in the presence of a peroxidase, causes a color change in a redox indicator which color change is proportional to the level of glucose in the test fluid.
  • colorimetric tests can be made semi-quantitative by the use of color charts for comparison of the color change of the redox indicator with the color change obtained using test fluids of known glucose concentration, and can be rendered more highly quantitative by reading the result with a spectrophotometric instrument, the results are generally not as accurate nor are they obtained as quickly as those obtained using an electrochemical biosensor.
  • biosensor is intended to refer to an analytical device that responds selectively to analytes in an appropriate sample and converts their concentration into an electrical signal via a combination of a biological recognition signal and a physico-chemical transducer.
  • a biosensor is an instrument which generates an electrical signal directly thereby facilitating a simplified design.
  • a biosensor offers the advantage of low material cost since a thin layer of chemicals is deposited on the electrodes and little material is wasted.
  • H 2 O 2 ⁇ O 2 + 2H + + 2e - (B) The electron flow is then converted to the electrical signal which directly correlates to the glucose concentration.
  • glucose present in the test sample converts the oxidized flavin adenine dinucleotide (FAD) center of the enzyme into its reduced form, (FADH 2 ). Because these redox centers are essentially electrically insulated within the enzyme molecule, direct electron transfer to the surface of a conventional electrode does not occur to any measurable degree in the absence of an unacceptably high overvoltage.
  • An improvement to this system involves the use of a nonphysiological redox coupling between the electrode and the enzyme to shuttle electrons between the (FADH 2 ) and the electrode.
  • GO(FAD) represents the oxidized form of glucose oxidase and GO(FADH 2 ) indicates its reduced form.
  • the mediating species M red shuttles electrons from the reduced enzyme to the electrode thereby oxidizing the enzyme causing its regeneration in situ which, of course, is desirable for reasons of economy.
  • the main purpose for using a mediator is to reduce the working potential of the sensor. An ideal mediator would be re-oxidized at the electrode at a low potential under which impurity in the chemical layer and interfering substances in the sample would not be oxidized thereby minimizing interference.
  • mediators are useful as mediators due to their ability to accept electrons from the reduced enzyme and transfer them to the electrode.
  • mediators known to be useful as electron transfer agents in analytical determinations are the substituted benzo- and naphthoquinones disclosed in U.S. Patent 4,746,607 ; the N-oxides, nitroso compounds, hydroxylamines and oxines specifically disclosed in EP 0 354 441 ; the flavins, phenazines, phenothiazines, indophenols, substituted 1,4-benzoquinones and indamins disclosed in EP 0 330 517 and the phenazinium/phenoxazinium salts described in U.S. Patent 3,791,988 .
  • a comprehensive review of electrochemical mediators of biological redox systems can be found in Analytica Clinica Acta. 140 (1982), Pp 1-18 .
  • hexacyanoferrate also known as ferricyanide
  • ferricyanide which is discussed by Schläpfer et al in Clinica Chimica Acta., 57 (1974), Pp. 283-289 .
  • U.S. Patent 4,929,545 there is disclosed the use of a soluble ferricyanide compound in combination with a soluble ferric compound in a composition for enzymatically determining an analyte in a sample.
  • Substituting the iron salt of ferricyanide for oxygen in equation (A) provides: since the ferricyanide is reduced to ferrocyanide by its acceptance of electrons from the glucose oxidase enzyme.
  • the electrons released are directly proportional to the amount of glucose in the test fluid and can be related thereto by measurement of the current which is produced upon the application of a potential thereto. Oxidation of the ferrocyanide at the anode renews the cycle.
  • US 5,508,171 discloses an electrochemical biosensor.
  • the electrochemical biosensor has a pair of electrodes consisting of a working electrode and a counter electrode and includes a sample receiving portion. A portion of the electrode surfaces is covered by a reagent that includes a redox mediator and an enzyme.
  • a fluid that contains an analyte such as glucose is added to the sample receiving portion.
  • a reaction involving the analyte, enzyme and redox mediator occurs. After this reaction is complete, an electrical potential difference is applied between the electrodes. Diffusion limited current is measured and correlated to the concentration of analyte in the fluid.
  • the glucose concentration measurement may be corrected for differences between environmental temperature at the time of actual measurement and the environmental temperature at the time calibration was performed.
  • Important objects of the present invention are to provide a new and improved method and apparatus for correcting ambient temperature effect in electrochemical enzyme-based biosensors; to provide such method and apparatus that eliminates or minimizes the ambient temperature effect in analyte concentration value identified by an electrochemical enzyme-based biosensor; and to provide such method and apparatus that overcome many of the disadvantages of prior art arrangements.
  • a method and apparatus are provided for correcting ambient temperature effect in electrochemical enzyme-based biosensors.
  • An ambient temperature value is measured.
  • a sample is applied to the biosensors, then a current generated in the test sample is measured.
  • An observed analyte concentration value is calculated from the current through a standard response curve. The observed analyte concentration is then modified utilizing the measured ambient temperature value to thereby increase the accuracy of the analyte determination.
  • G 1 is said observed analyte concentration value
  • T 2 is said measured ambient temperature value
  • I1, I2, S1, and S2 are predetermined parameters.
  • Biosensor system 100 includes a microprocessor 102 together with an associated memory 104 for storing program and user data.
  • a meter function 106 coupled to biosensor 108 is operatively controlled by the microprocessor 102 for recording test values, such as blood glucose test values.
  • An ON/OFF input at a line 110 responsive to the user ON/OFF input operation is coupled to the microprocessor 102 for performing the blood test sequence mode of biosensor system 100.
  • a system features input at a line 112 responsive to a user input operation is coupled to the microprocessor 102 for selectively performing the system features mode of biosensor 100.
  • a signal input indicated at a line 120 is coupled to the microprocessor 102 providing temperature information from a thermistor 122 in accordance with the invention.
  • Microprocessor 102 contains suitable programming to perform the methods of the invention as illustrated in FIG. 2 .
  • a display 150 is coupled to the microprocessor 102 for displaying information to the user including test results.
  • a battery monitor function 160 is coupled to the microprocessor 102 for detecting a low or dead battery condition.
  • An alarm function 162 is coupled to the microprocessor 102 for detecting predefined system conditions and for generating alarm indications for the user of biosensor system 100.
  • a data port or communications interface 164 couples data to and from a connected computer (not shown).
  • biosensor system 100 performs a temperature correction method of the preferred embodiment.
  • logical steps performed in accordance with the method for correcting ambient temperature effect in biosensors 108 by the biosensor processor 102 begin at block 200.
  • First ambient temperature is measured as indicated at a block 202 labeled MEASURE INSTRUMENT TEMPERATURE T2.
  • sensor current is measured as indicated at a block 204.
  • the measured current value is converted into an analyte concentration value, such as glucose concentration value (observed concentration), as indicated at a block 206.
  • correction for temperature effect is performed in a final glucose concentration calculation as indicated at a block 208.
  • G 1 is said observed analyte concentration value
  • T 2 is said measured ambient temperature value
  • I1, I2, S1, and S2 are predetermined parameters. This completes the sequence as indicated at a block 210.
  • Amperometric biosensors 108 are known to be sensitive to temperature. This temperature effect occurs because diffusion of the mediator to the working electrode is temperature dependent. Diffusion typically induces a temperature effect of 1 - 2% bias per degree centigrade. Therefore temperatures as low as 10°C would produce results with a bias of about -25% and temperatures as high as 40°C would produce results with a bias about +25%.
  • the system 100 instrument provides results between 0 to 50°C. The only available temperature measurement comes from a thermistor inside the instrument. In order to reduce the temperature bias it was necessary to develop a temperature correction algorithm.
  • the temperature effect was determined experimentally by biosensor system 100 whole blood glucose assay over the entire glucose (50 to 600 mg/dL) and temperature range (10 to 40°C) expected to be encountered. Actual blood glucose readings and sample temperatures were measured. This was done for six different sensor 108 lots. When the "compound interest” temperature correction method was used, several lots had percent biases of -10% to -13% at the extreme temperatures.
  • the "compound interest” algorithm did not work well because the temperature coefficient, tc, changed with glucose concentration.
  • a "polynomial” correction algorithm was invented to handle the varying temperature coefficient problem. By using a polynomial correction algorithm, the percent bias was limited to within +/-10%. The equation for the polynomial correction method is described in Equation #2. The grand sum of the absolute bias for both methods indicated that the polynomial correction method had less overall bias. Also, at the very extreme temperatures of 2 and 49°C, the polynomial correction method had lower bias (below 13.5%) where as the compound interest method was as high as -25%.
  • the polynomial correction method provided an improvement over the "compound interest" correction method.
  • G 2 G 1 - T 2 2 - 24 2 * I ⁇ 2 - T 2 - 24 * I ⁇ 1 T 2 2 - 24 2 * S ⁇ 2 + T 2 - 24 * S ⁇ 1 + 1
  • G 1 is the observed glucose concentration
  • T 2 is the sample temperature
  • I1, I2, S1, and S2 are the predetermined coefficients.
  • Table 1 shows an example of the temperature correction results.
  • T 2 is the sample temperature.
  • G R is the reference glucose valve.
  • I is the measured current.
  • G 1 is the observed glucose concentration (without temperature correction).
  • %B is the percent bias without temperature correction.
  • G 2 is the temperature corrected glucose concentration.
  • %B c is the percent bias after temperature correction.
  • the data shows the percent bias before and after the correction algorithm was applied.
  • the algorithm and coefficients were able to reduce the percent bias at the extreme temperatures of 10 to 40°C to within +/-7%.
  • thermocouple was inserted into a sensor without chemistry, and temperature data was collected every second after the blood was added to the sensor.
  • Table 2 Lot C Actual YSI Glucose and Current Response Sample Temp. YSI Current Slope Intercept 8.7°C 54.2 1063 8.7°C 412.5 4358 9.20 564.6 16.7°C 54.9 1148 16.7°C 414.9 4750 9.98 610.2 23.9°C 55.7 1223 23.9°C 418 5359 11.42 587.1 30.6oC 49.3 1203 30.6oC 408.4 5787 12.77 573.7 38.2oC 51.6 1275 38.2oC 418.7 6833 15.14 493.8
  • Table 3 Lot C - Current Through the YSI 50 and 400 mg/dL Curves and the Observed Glucose mg/dL Through the 24°C Curve YSI 23.9°C Curve Sample Reference Observed Temperature °C Glucose mg/dL Current Glucose mg/dL 8.7 50 1024 38.3 8.7 100 1484 78.6 8.7 200 2404 159.1 8.7 400 4243 320.1 8.7 600 6082 481.2 16.7 50 1109 45.7 16.7 100 1608 89.4 16.7 200 2606 176.8 16.7 400 4602 351.6 16.7 600 6598 526.4 23.9 50 1158 50.0 23.9 100 1729 100.0 23.9 200 2871 200.0 23.9 400 5155 400.0 23.9 600 7439 600.0 30.6 50 1212 57.7 30.6 100 1851 110.6 30.6 200 3128 222.5 30.6 400 5682 446.1 30.6 600 8236 669.8 38.2 50 1251 58.1 38.2 100 2008 12
  • the observed glucose concentration (G 1 ) was plotted against the sample temperature (T 2 ).
  • the 2nd order polynomial curve was used to fit the plot and the a1 and a2 constants for that level of glucose were obtained as provided in Table 4.
  • a computer program such as Slidewrite by Advanced Graphics Software Inc., or any other equivalent curve fitting program can be used.
  • Table 4 Lot C - 2nd Order Polynomial Coefficients 50 100 200 400 600 Coefficient mg/dL mg/dL mg/dL mg/dL mg/dL a0 29.689 68.654 146.318 301.709 457.305 a1 1.08071 1.06138 1.04494 1.00696 0.95187 a2 -0.00881 0.01035 0.04829 0.12417 0.20045 Corr.Coef.R 0.9990 1.000 0.9998 0.9996 0.9995
  • the a1 values obtained for the different levels of glucose were plotted against the glucose concentration.
  • the data was plotted using a linear fit, and the coefficients S1 (slope of the linear fit) and I1 (intercept of the linear fit) were generated.
  • the Slidewrite program on a PC by Advanced Graphics Software Inc., or any other equivalent curve fitting program can be used.
  • the a2 values obtained for the different levels of glucose were also plotted against the glucose concentration.
  • the data was plotted using a linear fit, and the coefficients S2 (slope of the linear fit) and I2 (intercept of the linear fit) were generated.
  • G 1 T 2 2 * a ⁇ 2 + T 2 * a ⁇ 1 + a ⁇ 0
  • G 2 24 2 * a ⁇ 2 + 24 * a ⁇ 1 + a ⁇ 0

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Claims (14)

  1. Procédé pour corriger l'effet de la température ambiante dans des biocapteurs électrochimiques basés sur des enzymes, comprenant les étapes qui consistent :
    à mesurer une valeur (202) de la température ambiante ;
    à appliquer un échantillon aux biocapteurs et à mesurer un courant généré dans l'échantillon d'essai (204) ;
    à calculer une valeur de concentration d'analyte en utilisant ladite valeur de température ambiante mesurée pour augmenter ainsi la précision de la détermination (206, 208) de l'analyte,
    caractérisé en ce que
    l'étape (206, 208) de calcul de ladite valeur de concentration d'analyte comprend l'étape (208) de conversion dudit courant mesuré en une valeur observée de concentration d'analyte et de calcul d'une valeur corrigée de concentration d'analyte en utilisant l'équation : G 2 = G 1 - T 2 2 - 24 2 * I ⁢ 2 - T 2 - 24 * I ⁢ 1 T 2 2 - 24 2 * S ⁢ 2 + T 2 - 24 * S ⁢ 1 + 1
    Figure imgb0016
    où G1 est ladite valeur observée de concentration d'analyte, T2 est ladite valeur mesurée de la température ambiante et I1, I2, S1 et S2 sont des valeurs de réglage.
  2. Procédé pour corriger l'effet de la température ambiante dans des biocapteurs selon la revendication 1, dans lequel I1, I2, S1 et S2 sont des coefficients déterminés expérimentalement.
  3. Procédé pour corriger l'effet de la température ambiante dans des biocapteurs selon la revendication 1 ou 2, dans lequel l'analyte est du glucose.
  4. Procédé pour corriger l'effet de la température ambiante dans des biocapteurs selon l'une des revendications 1 à 3, dans lequel l'étape (208) de calcul de ladite valeur de concentration d'analyte comprend l'étape de résolution d'une équation polynomiale ; ladite équation polynomiale comprenant ladite valeur mesurée de la température ambiante.
  5. Procédé pour corriger l'effet de la température ambiante dans des biocapteurs selon la revendication 4, dans lequel ladite équation polynomiale comprend une valeur mesurée et convertie de courant et des coefficients prédéfinis déterminés expérimentalement.
  6. Appareil (100) pour corriger l'effet de la température ambiante dans des biocapteurs électrochimiques basés sur des enzymes, comportant :
    un moyen (122) destiné à mesurer une valeur de la température ambiante ;
    un moyen (106, 108) réagissant à un échantillon appliqué aux biocapteurs électrochimiques basés sur des enzymes, pour mesurer un courant généré dans l'échantillon d'essai ; et
    un moyen (102) destiné à calculer une valeur de concentration d'analyte en utilisant ladite valeur mesurée de la température ambiante pour augmenter ainsi la précision de la détermination de l'analyte,
    caractérisé en ce que
    ledit moyen (102) destiné à calculer ladite valeur de concentration d'analyte comprend un moyen destiné à convertir ledit courant mesuré en une valeur observée de concentration d'analyte et à calculer une valeur corrigée de concentration d'analyte en utilisant l'équation : G 2 = G 1 - T 2 2 - 24 2 * I ⁢ 2 - T 2 - 24 * I ⁢ 1 T 2 2 - 24 2 * S ⁢ 2 + T 2 - 24 * S ⁢ 1 + 1
    Figure imgb0017
    où G1 est ladite valeur observée de concentration d'analyte, T2 est ladite valeur mesurée de la température ambiante et I1, I2, S1 et S2 sont des valeurs définies.
  7. Appareil (100) pour corriger l'effet de la température ambiante dans des biocapteurs selon la revendication 6, comprenant un moyen à processeur (102) destiné à effectuer une séquence d'essai prédéfinie ; et dans lequel ledit moyen (122) destiné à mesurer ladite valeur de température ambiante comprend une thermistance couplée audit moyen à processeur (102).
  8. Appareil (100) pour corriger l'effet de la température ambiante dans des biocapteurs selon la revendication 6 ou 7, dans lequel ledit moyen (102) destiné à calculer ladite valeur de concentration d'analyte comprend un moyen destiné à résoudre une équation polynomiale ; ladite équation polynomiale comprenant ladite valeur mesurée de la température ambiante.
  9. Appareil (100) pour corriger l'effet de la température ambiante dans des biocapteurs selon l'une des revendications 6 à 8, dans lequel ladite équation polynomiale comprend une valeur de courant mesurée et convertie et des coefficients prédéterminés déterminés expérimentalement.
  10. Appareil (100) pour corriger l'effet de la température ambiante dans des biocapteurs selon la revendication 9, dans lequel I1, I2, S1 et S2 sont des coefficients déterminés expérimentalement.
  11. Appareil (100) pour corriger l'effet de la température ambiante dans des biocapteurs selon l'une des revendications 6 à 10, dans lequel l'analyte est du glucose.
  12. Appareil (100) pour corriger l'effet de la température ambiante dans des biocapteurs selon l'une des revendications 6 à 11, dans lequel ledit moyen (106, 108) qui réagit audit échantillon appliqué aux biocapteurs, destiné à mesurer ledit courant généré dans l'échantillon d'essai, est couplé audit moyen à processeur (102) pour recevoir un signal représentant ledit courant généré dans l'échantillon d'essai.
  13. Appareil (100) pour corriger l'effet de la température ambiante dans des biocapteurs selon l'une des revendications 6 à 12, dans lequel ledit moyen (102) destiné à calculer ladite valeur de concentration d'analyte comprend un moyen à processeur couplé audit moyen (122) de mesure de la température ambiante et audit moyen (106, 108) de mesure du courant, et comprenant un moyen destiné à résoudre une équation prédéterminée utilisant lesdites valeurs mesurées et lesdites valeurs de coefficients prédéterminées.
  14. Biocapteur électrochimique à base d'enzyme comportant :
    un moyen à biocapteur électrochimique à base d'enzyme destiné à recevoir un échantillon d'utilisateur ; et
    l'appareil (100) selon l'une des revendications 6 à 13.
EP98107778A 1997-05-12 1998-04-29 Méthode et appareil pour corriger l'effet de la température ambiente dans les biodétecteurs Expired - Lifetime EP0878713B1 (fr)

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EP20090000924 EP2048499A1 (fr) 1997-05-12 1998-04-29 Méthode et appareil pour corriger l'effet de la température ambiente dans les biodétecteurs

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US08/854,440 US6391645B1 (en) 1997-05-12 1997-05-12 Method and apparatus for correcting ambient temperature effect in biosensors
US854440 1997-05-12

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CA2236314A1 (fr) 1998-11-12
AU6481898A (en) 1998-11-12
AU729232B2 (en) 2001-01-25
EP0878713A2 (fr) 1998-11-18
EP2048499A1 (fr) 2009-04-15
US6391645B1 (en) 2002-05-21
ES2321348T3 (es) 2009-06-04
TW565695B (en) 2003-12-11
CA2236314C (fr) 2004-02-10
JP4124513B2 (ja) 2008-07-23
JPH10318963A (ja) 1998-12-04
EP2264451A1 (fr) 2010-12-22
DK0878713T3 (da) 2009-06-02
DE69840614D1 (de) 2009-04-16
NZ329792A (en) 1999-02-25
EP0878713A3 (fr) 2004-06-23

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